The present invention relates to 1,2-disubstituted ethyl amides useful in the treatment and prevention of atherosclerosis.
Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, cigarette smoking and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk.
Cholesterol esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesterol esters is also a key step in the intestinal absorption of dietary cholesterol. The intracellular esterification of cholesterol is catalyzed by the enzyme acyl CoA:cholesterol acyl transferase (ACAT, EC 2.3.1.26). Thus, inhibition of ACAT is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesterol esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
A number of amides have been reported as being useful in lowering cholesterol and/or in inhibiting the formation of cholesterol-containing lesions in mammalian arterial walls. U.S. Pat. No. 3,784,577 to Fukurmaru et al discloses fatty acid amide derivatives of the formula R-CONHR.sup.1 wherein RCO is a fatty acid radical and R.sup.1 is 1-.alpha.-benzylbenzyl.
U.S. Pat. No. 4,603,145 to De Vries et al discloses diaryl alkanamides of the formula ##STR2## wherein R.sup.3 and R.sup.4 independently include benzyl and phenethyl.
U.S. Pat. No. 4,420,475 to Damon et al discloses silicon-bearing amides of the formula ##STR3## wherein R.sup.1, R.sup.2 and R.sup.3 independently can be alkyl, phenyl, benzyl or phenethyl and R can be 1-.alpha.-benzylbenzyl optionally substituted in the phenyl rings. U.S. Pat. No. 4,434,161 to Barcza discloses similar compounds having a sulfur atom in the chain between the silicon atom and the carbonyl group.
U.S. Pat. No. 4,456,619 to Kathawala discloses amides of 2-alkynoic acids of the formula ##STR4## wherein A is alkyl, alkenyl or cyclopropanyl-substituted alkyl and B can be 1-.alpha.-benzylbenzyl, optionally substituted in the phenyl rings.
U.S. Pat. No. 4,716,175 to Hoefle et al discloses fatty acid amides of the formula ##STR5## wherein A is an alkyl chain, R.sup.1 and R.sup.2 can each be phenylmethyl, and B can be phenyl, benzyl, pyrimidinyl or pyridyl.
U.S. Pat. No. 4,518,789 to Yu et al discloses dermatologically useful phenyl alpha-acyloxyacetamides of the formula ##STR6## wherein R.sup.1 and R.sup.2 can be hydrogen, alkyl or araikyl and R.sup.3 and R.sup.4 can be hydrogen, alkyl, aralkyl or aryl.
While some of these diphenylethylamides have shown in vitro ACAT inhibitory activity, none have been reported to show significant activity in whole animal models of atherosclerosis.
In addition, U.S. Pat. No. 5,149,709 discloses compounds, having in vivo anti-atherosclerotic activity, of the formula ##STR7## wherein R.sub.1 and R.sub.2 are independently a heteroaryl group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, triazinyl, imidazolyl, thiophenyl, oxazolyl and furanyl; X-substituted heteroaryl wherein X is 1 to 3 substituents independently selected from the group consisting of halogeno, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, lower dialkylamino, acetamido, methanesulfonyl-amino, 2-(trimethylsilyl)ethoxymethyl, carboxy and lower alkoxycarbonyl; X-substituted phenyl; or N-substituted triazinyl or N-substituted imidazolyl wherein the N-substituents are selected from the group consisting of lower alkyl, 2-(trimethylsilyl)ethoxymethyl and R.sub.5 CO-- wherein R is lower alkyl, phenyl, benzyl or 2,2-dimethylpropyl;
and in addition, one of R.sub.1 and R.sub.2 can be as defined above and the other can be phenyl;
R.sub.3 is an alkyl chain of 1 to 25 carbon atoms, branched or straight, saturated or containing one or more double bonds; an alkyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, X-substituted phenyl, heteroaryl and X-substituted heteroaryl; an alkyl chain as defined interrupted by one or more groups independently selected from the group consisting of --O--, --S--, --SO--, --SO.sub.2 --, --NH--, --N(lower alkyl)--, --C(O)--, phenylene, X-substituted phenylene, heteroarylene and X-substituted heteroarylene; or an interrupted alkyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, X-substituted phenyl, heteroaryl and X-substituted heteroaryl; PA1 R.sub.4 is hydrogen, lower alkyl, phenyl, X-substituted phenyl, heteroaryl or X-substituted heteroaryl; or a pharmaceutically acceptable salt thereof. PA1 A is phenyl, Q-substituted phenyl, heteroaryl, or Q-substituted heteroaryl, wherein Q is 1 to 3 substituents independently selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, halogeno, --COOH, --CONH.sub.2, R.sup.8 O--C(O)--, R.sup.8 NH--C(O)--, (R.sup.8).sub.2 N--C(O)--, R.sup.8 NH--, (R.sup.8).sub.2 N-- and R.sup.8 --C(O)--NH--, wherein R.sup.8 is lower alkyl; PA1 B is cycloalkyl, Y-substituted cycloalkyl, heterocycloalkyl, or Y-substituted heterocycloalkyl, wherein: Y is 1 to 3 substituents independently selected from the group consisting of alkyl, hydroxy, --COOH, --CONH.sub.2, R.sup.8 O--C(O)--, R.sup.8 NH--C(O)--, (R.sup.8).sub.2 N--C(O)--, O.dbd., HO--N.dbd., CF.sub.3 C(O)NH--, CH.sub.3 C(O)CH.sub.2 C(O)O--, CH.sub.3 C(O)O--, R.sup.5 O--, --S(O).sub.m --R.sup.5, --NH.sub.2, R.sup.5 NH--, (R.sup.5).sub.2 N-- and R.sup.5 --C(O)--NH--, wherein m is 0, 1 or 2, R.sup.5 is lower alkyl, phenyl or Q-substituted phenyl, and R.sup.8 is as defined above; or Y is a bivalent group of the formula --O--(CH.sub.2).sub.2 --O--, or --(CH.sub.2).sub.4 --, wherein both termini of the bivalent group are attached to the same carbon atom, thereby constituting a spiro-fused substituent; PA1 R.sup.3 is an alkyl chain of 1 to 25 carbon atoms, branched or straight; an alkenyl chain of 2 to 25 carbon atoms, branched or straight; an alkyl or alkenyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, Q-substituted phenyl, phenoxy, heteroaryl and Q-substituted heteroaryl; an alkyl or alkenyl chain as defined interrupted by one or more groups independently selected from the group consisting of --O--, --S(O).sub.m --, --NH--, --N(R.sup.5)--, --C(O)--, phenylene, Q-substituted phenylene, heteroarylene and Q-substituted heteroarylene; or an interrupted alkyl chain or interrupted alkenyl chain as defined substituted by one or more substituents selected from the group consisting of phenyl, Q-substituted phenyl, heteroaryl and Q-substituted heteroaryl; PA1 R.sup.4 is hydrogen, lower alkyl, phenyl, Q-substituted phenyl, heteroaryl or Q-substituted heteroaryl; PA1 R.sup.6 and R.sup.7 are both H, or R.sup.6 and R.sup.7 together represent .dbd.O; PA1 "halogeno" refers to fluorine, chlorine, bromine or iodine radicals; PA1 "cycloalkyl" means a saturated carbocyclic ring having from 3 to 9, preferably from 3 to 6, carbon atoms; PA1 "heterocycloaikyl" means a cycloalkyl group in which 1 to 3 ring members are heteroatoms selected from N, S and O, such as pyrrolidinyl, piperidinyl, morpholino, piperazinyl or piperidonyl; PA1 "phenylene" means a bivalent phenyl group bound in an ortho, meta or para orientation; PA1 "heteroaryl" means an aromatic group having from 2 to 14, preferably from 2 to 9, carbon atoms and from 1 to 3 heteroatoms, selected from O, N and S, such as pyridyl, furanyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiadizolyl, benzofuranyl, indolyl, benzothienyl, pyrazolyl or oxazolyl; and PA1 "heteroarylene" means a bivalent heteroaryl group.